Abstract Nausea and vomiting occurs in up to 80% of pregnancies in the US. About one third of women with nausea and vomiting of pregnancy (NVP) have symptoms that are clinically significant, causing increased maternal stress, decreased quality of life and work loss. A small percentage will develop hyperemesis gravidarum, the most severe form of NVP, which often requires hospitalization. Early treatment of NVP is recommended to stop progression to hyperemesis gravidarum. Although not formally approved for the treatment of NVP, ondansetron - a 5-HT3 receptor antagonist blocking the effect of serotonin - rapidly became the most frequently prescribed drug for NVP in the US because of its perceived superior effectiveness and improved side-effect profile . NVP and hyperemesis gravidarum typically occur during the first trimester, the most sensitive time for exposure to teratogens. Unfortunately, the available evidence on the fetal safety of ondansetron is limited and conflicting. Some recent studies have reported a doubling in risk of cleft palate and heart defects in newborns exposed to ondansetron during pregnancy. However, residual confounding bias has been posited as a potential explanation for these findings. Such conflicting data leave pregnant women and their clinicians unsure with respect to the appropriate risk-benefit trade-off for ondansetron. The objective of the proposed study is to help fill this information gap by examining the two most important safety concerns that have been raised regarding first trimester ondansetron exposure: (1) major cardiac malformations, and (2) oral clefts. We will utilize a large national cohort of approximately 1.6 million Medicaid insured pregnant women and linked infants for 2000-2013 (the most recent Medicaid data available), which includes approximately 50,000 women exposed to ondansetron during the first trimester. We will use fine stratification on the propensity score and the high-dimensional propensity score to account for potential confounding and will conduct a series of sensitivity analyses to evaluate the impact of potential misclassification of the exposure and the outcome on the findings. This effort will make use of an existing national cohort of pregnancies and will build upon the experience of a multidisciplinary research team - a collaboration between Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health - to contribute urgently needed information on the safety of this widely used medication during pregnancy. By clarifying the risk associated with this medication, the study will have a direct impact on clinical practice.